title: Down-regulation of miR-301a suppresses pro-inflammatory cytokines in Toll-like receptor-triggered macrophages.
abstract: In many types of tumours, especially pancreatic adenocarcinoma, miR-301a is over-expressed. This over-expression results in negative regulation of the target gene of miR-301a, the nuclear factor-κB (NF-κB) repressing factor (NKRF), increasing the activation of NF-κB and production of NF-κB-responsive pro-inflammatory cytokines such as interleukin-8, interferon-β, nitric oxide synthase 2A and cytochrome oxidase subunit 2 (COX-2). However, in immune cells, mechanisms that regulate miR-301a have not been reported. Similar to tumour cells, Toll-like receptor (TLR) -activated macrophages produce NF-κB-responsive pro-inflammatory cytokines. Therefore, it is of considerable interest to determine whether miR-301a regulates the secretion of cytokines by immune cells. In the present study, we demonstrate that the expression of miR-301a was decreased in TLR-triggered macrophages. Through targeting NKRF, miR-301a affected the activity of NF-κB and the expression of pro-inflammatory genes downstream of NF-κB such as COX-2, prostaglandin E2 and interleukin-6. In addition, when lipopolysaccharide-treated macrophages were simultaneously stimulated with trichostatin A, an inhibitor of histone deacetylases, the expression of miR-301a increased, whereas NKRF and pro-inflammatory cytokine expression decreased. However, further investigation revealed that there was no correlation between the induction of miR-301a and the inhibitory effect of trichostatin A on lipopolysaccharide-induced gene expression in macrophages. In summary, our study indicates a new mechanism by which miR-301a regulates inflammatory cytokine expression in macrophages, which may clarify the regulatory role of microRNAs in immune-mediated inflammatory responses.
authors.affiliation: Emergency Department of Navy General Hospital, Beijing, China.
authors.forename: Lisong
authors.initials: L
authors.lastname: Huang
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.forename: Liqiu
authors.initials: L
authors.lastname: Wang
authors.forename: Ruifeng
authors.initials: R
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Ge
authors.forename: Zhusen
authors.initials: Z
authors.lastname: Lin
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Shan
authors.forename: Qingxian
authors.initials: Q
authors.lastname: Lin
authors.forename: Minghong
authors.initials: M
authors.lastname: Jiang
mesh_terms: D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D056545:Group III Histone Deacetylases / Q000037:antagonists & inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D016207:Cytokines; D006877:Hydroxamic Acids; D018836:Inflammation Mediators; C573832:MIRN301 microRNA, mouse; D035683:MicroRNAs; D016328:NF-kappa B; C111027:NKRF protein, human; D012097:Repressor Proteins; D051193:Toll-Like Receptors; C012589:trichostatin A; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D056545:Group III Histone Deacetylases
keywords: Toll-like receptor; histone deacetylase inhibitor; inflammatory response; macrophage; miR-301a; nuclear factor-κB-repressing factor